Elastomeric functional biodegradable copolyester amides and copolyester urethanes

ABSTRACT

The present invention provides elastomeric copolyester amides, elastomeric copolyester urethanes, and methods for making the same. The polymers that are based on α-amino acids and possess suitable physical, chemical and biodegradation properties. The polymers are useful as carriers of drugs or other bioactive substances.

BACKGROUND OF THE INVENTION

While they potentially offer many advantages due to their “organicnature,” conventional poly(α-amino acids) possess many undesirablephysical, chemical and biodegradation properties. For example, thebiological and material properties of conventional poly(α-amino acids)cannot be varied over a wide range. In addition, the synthesis of manyconventional poly(α-amino acids) is difficult and expensive.

A considerable amount of attention has therefore been focussed onreplacing the amide (peptide) linkage in the conventional poly(α-aminoacids) with a variety of non-amide bond to provide novel polymericsystems that are based on α-amino acids. One class of α-amino acidderived polymers are polyisopeptides (alternatively known aspseudo-poly(amino acids)), which belong to the XY-type heterochainpolymers. Polyisopeptides are usually foamed by linking trifunctionalα-amino acids in the backbone chains. However, relatively few attemptshave been made to synthesize polyisopeptides. For example, Sekiguchi etal. obtained poly-β-(α-alkyl-L-aspartate) by the ring-openingpolymerization of β-lactams. See, Rodriguez-Galan, A. et al., Makromol.Chem., Makromol. Symp., 6, 277 (1986) and Vives, J. et al., Makromol.Chem., Rapid Commun., 10(1):13 (1989). One major limiting feature ofpolyisopeptides is that structural modifications are limited solely tochemical variations at the N-acyl residue of the polyisopeptide. Thisnarrow range of chemical modification has resulted in an undesirablynarrow range of material properties of these polymers.

Another class of α-amino acid derived polymers are amino acid basedbioanalagous polymers (AABBPs), which belong to the XX-YY heterochainpolymers. AABBPs are mainly obtained by the polycondensation of XX (onetype of monomer having two X functional groups) and YY (another type ofmonomer having two Y functional groups). AABBPs are not pure polyaminoacids or pseudo-polyamino acids because they include residues of othertypes of monomers (e.g., dicarboxylic acids and diols).

One class of AABBPs are poly(ester ureas) (PEUs), which are preparedfrom bis-α-aminoacyl diol monomers. The first attempt to usebis-α-aminoacyl(phenylalanyl) diol for preparing bioabsorbable,semi-physiological polymers similar to poly(ester urea) was by Huang etal. Huang S. J., et al., J. Appl. Polym. Sci., 23(2): 429 (1979). Onlylow-molecular-weight PEUs, having limited material properties, could beprepared by this route.

Lipatova et al. have also synthesized semi-physiological poly(esterurethane ureas) from bis-L-phenylalanyl diols, diols, and diisocyanates.Lipatova T. E., et al., Dokl. Akad. Nauk SSSR, 251(2): 368 (1980) andGladyr I. I., et al. Vysokomol. Soed., 31B(3): 196 (1989). However, noinformation on the synthesis of the starting material (e.g., α-diaminodiesters) was given.

Yoneyama et al. reported on the synthesis of high-molecular-weightsemi-physiological PEUs by the interaction of free α-diamino-diesterswith non-physiological diisocyanates. Yoneyama M., et al., Polym. Prepr.Jpn., 43(1): 177 (1994). Contrary to Huang et al. (Huang S. J., et al.,J. Appl. Polym. Sci., 23(2): 429 (1979)), high-molecular-weight PEUswere obtained in some cases. In view of this preliminary data, thereremains an ongoing need for novel polymers based on α-amino acids thatpossess a wide range of physical, chemical and biodegradationproperties.

SUMMARY OF THE INVENTION

The present invention provides polymers that are based on α-amino acids.In contrast to conventional poly(α-amino acids), the polymers of thepresent invention (e.g., elastomeric functional copolyester amides andcopolyester urethanes) possess advantageous physical, chemical andbiodegradation properties. For example, the polymers of the presentinvention possess suitable biodegradation (weight loss percent)properties under varying conditions, (see, Table III). The hydrolysis ofthe polymers can be catalyzed by hydrolases (e.g., trypsin,α-chymotrypsin, lipase, etc.). As such, the polymers can be used ascarriers for covalent immobilization (attachment) of various drugs andother bioactive substances. In addition, the enzyme catalyzedbiodegradation rates of the polymer of the present invention can bechanged by varying the polymer composition (e.g., l/p ratio) and/or thenature of the functional groups (e.g., dicarboxylic acids, diols, orα-amino acids).

The present invention provides a polymer of formula (VII):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R¹ is independently (C₂-C₂₀)alkylene;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

each R⁴ is independently (C₂-C₂₀)alkylene; comprising one or moresubunits of the formula (I):

 and one or more subunits of the formula (II):

 wherein

the combined number of subunits (I) and (II) is about 50 to about 150.

Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂;R² can independently be hydrogen or benzyl; each R³ can independently beiso-butyl or benzyl; and R⁴ can independently be (CH₂)₄, (CH₂)₆, (CH₂)₈,or (CH₂)₁₂.

The present invention also provides a polymer of formula (VII):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R¹ is independently (C₂-C₂₀)alkylene;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

each R⁴ is independently (C₂-C₂₀)alkylene.

Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂;each R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; p/(p+m) can be about 0.9 to about0.1; and m/(p+m) can be about 0.1 to about 0.9.

The present invention also provides a polymer of formula (VII) formedfrom an amount of one or more compounds of formula (III):

wherein

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

R⁴ is independently (C₂-C₂₀)alkylene; or a suitable salt thereof; and anamount of one or more compounds of formula (IV):

 wherein

R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or a suitablesalt thereof; and

an amount of one or more compounds of formula (V):

wherein

R¹ is independently (C₂-C₂₀)alkylene; and

each R⁵ is independently (C₆-C₁₀)aryl, optionally substituted with oneor more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy.

Specifically, R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂; R² canindependently be hydrogen or benzyl; each R³ can independently beiso-butyl or benzyl; R⁴ can independently be (CH₂)₄, (CH₂)₆, (CH₂)₈, or(CH₂)₁₂; each R⁵ can independently be p-nitrophenyl; the compound offormula (III) can be the di-p-tolunesulfonic acid salt of abis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula (IV)can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester; andthe compound of formula (V) can be di-p-nitrophenyl adipate,di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate.

The present invention also provides a method for preparing a polymer offormula (VII):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R¹ is independently (C₂-C₂₀)alkylene;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

each R⁴ is independently (C₂-C₂₀)alkylene; comprising contacting anamount of one or more compounds of formula (III):

 or a suitable salt thereof; and

an amount of one or more compounds of formula (IV):

or a suitable salt thereof; and

an amount of one or more compounds of formula (V):

wherein

each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one ormore nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy;

under suitable conditions to provide the polymer of formula (VII).

Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂;each R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can be p-nitrophenyl; thecompound of formula (III) can be the di-p-tolunesulfonic acid salt of abis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula (IV)can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester; thecompound of formula (V) can be di-p-nitrophenyl adipate,di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate;p/(p+m) can be about 0.9 to about 0.1; and m/(p+m) can be about 0.1 toabout 0.9. The contacting can be carried out in the presence of a base,wherein the base can be triethylamine. The contacting can also becarried out in the present, of a solvent, wherein the solvent can beN,N-dimethylacetamide. The contacting can also be carried out at atemperature of about 50° C. to about 100° C. The contacting canpreferably occur for about 10 hours to about 24 hours. The polymer offormula (VII) can also optionally be purified.

The present invention also provides a polymer of formula (XI):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R⁴ is independently (C₂-C₂₀)alkylene; and

each R⁶ is independently (C₁-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene;

comprising one or more subunits of the formula (VIII):

wherein

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

R⁴ is independently (C₂-C₂₀)alkylene;

R⁶ is independently (C₂-C₂₀)alkylene or (C₂-C₈)alkyloxy(C₂-C₂₀)alkylene;and

one or more subunits of the formula (IX):

wherein

the total number of subunits (VIII) and (IV) is about 50 to about 150;

R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl.

Specifically, R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; R⁴ can independently be (CH₂)₄,(CH₂)₆, (CH₂)₈ or (CH₂)₁₂; and R⁶ can independently be (CH₂)₃ or(CH₂)₂—O—(CH₂)₂.

The present invention also provides a polymer of formula (XI):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R⁴ is independently (C₂-C₂₀)alkylene; and

each R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene.

Specifically, each R² can independently be hydrogen or benzyl; each R³can independently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁶ can independently be (CH₂)₃or (CH₂)₂—O—(CH₂)₂; p/(p+m) can be about 0.9 to about 0.1; and m/(p+m)can be about 0.1 to about 0.9.

The present invention also provides a polymer of formula (XI) formedfrom an amount of one or more compounds of formula (III):

wherein each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

R⁴ is independently (C₂-C₂₀)alkylene; or a suitable salt thereof; and

an amount of one or more compounds of formula (IV):

wherein

R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or a suitablesalt thereof, and

an amount of one or more compounds of formula (X):

wherein

each R⁵ is independently (C₁-C₁₀)aryl optionally substituted with one ormore nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and

R⁶ is independently (C₂-C₂₀)alkylene or (C₂-C₈)alkyloxy(C₂-C₂₀)alkylene.

Specifically, R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; R⁴ can independently be (CH₂)₄,(CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can be p-nitrophenyl; R⁶ canindependently be (CH₂)₃ or (CH₂)₂—O—(CH₂)₂; the compound of formula(III) can be the di-p-tolunesulfonic acid salt of a bis-(L-α-aminoacid)-α,ω-alkylene diester; the compound of formula (IV) can be thedi-p-tolunesulfonic acid salt of L-lysine benzyl ester; the compound offormula (X) can be 1,3-bis(4-nitro-phenoxycarbonyloxy)propane; or2,2′-bis-4-nitrophenoxycarbonyloxy ethylether; p/(p+m) can be about 0.9to about 0.1; and m/(p+m) can be about 0.1 to about 0.9.

The present invention also provides a method for preparing a polymer offormula (XI):

wherein

is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R² is independently hydrogen or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R⁴ is independently (C₂-C₂₀)alkylene;

each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one ormore nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and

each R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene;

comprising contacting an amount of one or more compounds of formula(III):

or a suitable salt thereof; and

an amount of one or more compounds of formula (IV):

or a suitable salt thereof; and

an amount of one or more compounds of formula (X):

under suitable conditions to provide the polymer of formula (XI).

Specifically, each R² can independently be hydrogen or benzyl; each R³can independently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can be p-nitrophenyl; eachR⁶ can independently be (CH₂)₃ or (CH₂)₂—O—(CH₂)₂; the compound offormula (III) can be the di-p-tolunesulfonic acid salt of abis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula (IV)can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester; thecompound of formula (X) can be1,3-bis(4-nitro-phenoxycarbonyloxy)propane, or2,2′-bis-4-nitrophenoxycarbonyloxy ethylether; p/(p+m) can be about 0.9to about 0.1; and m/(p+m) can be about 0.1 to about 0.9. The contactingcan be carried out in the presence of a base, wherein the base can betriethylamine. The contacting can be carried out in the presence of asolvent, wherein the solvent can be N,N-dimethylacetamide. Thecontacting can be carried out at a temperature of about 50° C. to about100° C. The contacting can occur for about 10 hours to about 24 hours.In addition, the polymer of formula (XI) can optionally be purified.

The biodegradation of the copolyester amides and copolyester urethanesof the present invention allows the delivery of essential α-amino acidsto targeted sites (e.g., to facilitate wound repair of injured tissues).In addition, the polymers of the present invention can be used for theattachment free iminoxyl radicals for suppressing inconsolable cellproliferation, and heparin or hirudin for increasing hemocompatibility.These modified polymers can be used to coat stents to suppressrestenosis. In addition, the polymers of the present invention can beused as polyacids for the application in gynecology as impregnatedcontraceptive agents, e.g., for the controlled release of ferrousgluconate and the like. Furthermore, the polymers of the presentinvention can be used as polyacids for the attachment of unsaturatedcompounds, e.g., allyl amine or allyl alcohol, to obtain photo-curableand cross-linkable biodegradable polymers. The present polymers can becross-linked with other polymers containing double bonds to createhybrid materials.

The biological and material properties of the polymers of the presentinvention can be varied over a wide range because the polymers can beformed from starting materials having varying functional groups (e.g.,dicarboxylic acids, diols, and α-amino acids). See, e.g., Examples 1-22.In contrast to conventional poly(α-amino acids), the elastomericfunctional copolyester amides and copolyester urethanes of the presentinvention can be obtained in high yields. See, Table III. For example,the compounds of the present invention can be prepared in yields up toabout 97%. In addition, the reaction conditions employed to prepare thepolymers of the present invention are relatively simple and the reagentsare relatively inexpensive.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described: halo canbe chloro, fluoro, bromo, or iodo. Alkyl, alkenyl, alkynyl, etc. denoteboth straight and branched groups; but reference to an individualradical such as “propyl” embraces only the straight chain radical, abranched chain isomer such as “isopropyl” being specifically referredto.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof of a compound of the invention,which possess the useful properties described herein, it being wellknown in the art how to prepare optically active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase).

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. Examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. “Alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving two open valences and having the specified number of carbonatoms. Examples of alkylene include, but are not limited to, methylene,ethylene, n-propylene, n-butylene, s-butylene, and n-pentylene. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. Examples of alkoxyinclude, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration having one or more unsaturated carbon-carbon bonds, whichmay occur in any stable point along the chain, such as ethenyl andpropenyl. “Alkynyl” is intended to include hydrocarbon chains of eithera straight or branched configuration having one or more triplecarbon-carbon bonds, which may occur in any stable point along thechain, such as ethynyl and propynyl. “Aryl” denotes a phenyl radical oran ortho-fused bicyclic carbocyclic radical having about nine to tenring atoms in which at least one ring is aromatic. Examples of arylinclude, but are not limited to phenyl and naphthyl.

A specific value for R¹ is (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.

A specific value for R² is hydrogen, benzyl, sec-phenethyl, ormethylbenzyl. Another specific value for R² is benzyl.

A specific value for R³ is iso-butyl or benzyl.

A specific value for R⁴ is (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.

A specific value for R⁵ is p-nitrophenyl.

A specific value for R⁶ is (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.

A specific value for m is about 0.25 to about 0.75.

A specific value for p is about 0.75 to about 0.25.

A specific value for n is about 75 to about 125.

A specific value for p/(p+m) is about 0.75 to about 0.25.

A specific value for m/(p+m) is about 0.25 to about 0.75.

A specific value for (p+m) is about 0.9 to about 1.1. Another specificvalue for (p+m) is about 0.75 to about 1.25.

A specific group of compounds of formula (III) are thedi-p-tolunesulfonic acid salts of a bis-(L-α-amino acid)-α,ω-alkylenediester:

wherein

each R³ is independently is iso-butyl or benzyl; and

R⁴ is (CH₂)₄, (CH₂)₆, or (CH₂)₁₂.

A specific group of compounds of formula (IV) are thedi-p-tolunesulfonic acid salts of L-lysine arylalkyl esters:

wherein

R² is benzyl sec-phenethyl, or methylbenzyl. More specifically, R² canbe benzyl.

A specific group of compounds of formula (V) are compounds of theformula:

wherein

R¹ is (CH₂)₄, (CH₂)₈, or (CH₂)₁₂; and

R⁵ is p-nitrophenyl.

For example, a specific group of compounds of formula (V) aredi-p-nitrophenyl adipate, di-p-nitrophenyl sebacinate, anddi-p-nitrophenyl dodecyldicarboxylate

A specific group of compounds of formula (X) are compounds of theformula:

wherein

R⁵ is p-nitrophenyl; and

R⁶ is (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.

For example, a specific group of compounds of formula (X) are1,3-bis(4-nitro-phenoxycarbonyloxy)propane and2,2′-bis-4-(nitrophenoxycarbonyloxy)ethylether.

In cases where compounds (e.g., starting materials) are sufficientlybasic or acidic to form stable nontoxic acid or base salts, thecompounds can exist as the acceptable salt. Examples of acceptable saltsare organic acid addition salts formed with acids which form anacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosplhate. Suitable inorganic salts mayalso exist, including hydrochloride, sulfate, nitrate, bicarbonate, andcarbonate salts.

Acceptable salts may be obtained by using standard procedures that arewell known in the art, for example by reacting a sufficiently basiccompound such as an amine with a suitable acid affording an acceptableanion. Alkali metal (for example, sodium, potassium or lithium) oralkaline earth metal (for example calcium) salts of carboxylic acids canalso be made.

Processes for preparing polymers of the present invention (e.g.,polymers of formula (VII) and polymers of formula (XI)) are provided asfurther embodiments of the invention and are as illustrated by theprocedures herein below in which the meanings of the generic radicalsare as given above unless otherwise qualified.

A polymer of formula (VII) can include one or more subunits of formula(I) and one or more subunits of formula (II). As such, a polymer offormula (VII) can be prepared from a compound of formula (III), from acompound of formula (IV), and from a compound of formula (V).Specifically, a polymer of formula (VII) can be prepared by contacting acompound of formula (III), a compound of formula (IV), and a compound offormula (V) under suitable conditions to provide a polymer of formula(VII).

The compounds of formula (III), (IV), and (V) can be contacted in thepresence of a solvent. Any suitable solvent can be employed. When thecompounds of formula (III), (IV), and (V) are contacted in the presenceof a solvent, the compounds of formula (III), (IV), and (V) arepreferably soluble in the solvent. One exemplary suitable solvent isN,N-dimethylacetamide.

The compounds of formula (III), (IV), and (V) can be contacted in thepresence of base. Any suitable base can be employed. When the compoundsof formula (III), (IV), and (V) are contacted in the presence of a base,the base will preferably adjust the initial pH of the reaction mixture(i.e., the solution including the compounds of formula (III), (IV), and(V)) above about 7. The base is useful to yield the free amines of thecompound of formula (III) and the compound of formula (IV). Oneexemplary suitable base is triethylamine.

The compounds of formula (III), (IV), and (V) can be contacted for aperiod of time sufficient to provide the polymer of formula (II). Forexample, the period of time can be from about 1 hour to about 48 hours,inclusive. Preferably, the period of time can be from about 5 hours toabout 30 hours, inclusive. More preferably, the period of time can befrom about 10 hours to about 24 hours, inclusive.

The compounds of formula (III), (IV), and (V) can be contacted at atemperature sufficient to provide the polymer of formula (VII). Forexample, the temperature can be from the freezing point of the liquidreaction mixture (e.g., the solvent, base, and the compounds of formula(III), (IV), and (V)) up to about the reflux temperature of the reactionmixture. Preferably, the temperature can be from about 25° C. to about150° C. More preferably, the temperature can be from about 50° C. toabout 100° C.

A polymer of formula (XI) can include one or more subunits of formula(VIII) and one or more subunits of formula (IX). As such, a polymer offormula (XI) can be prepared from a compound of formula (III), from acompound of formula (IV), and from a compound of formula (X).Specifically, a polymer of formula (XI) can be prepared by contacting acompound of formula (III), a compound of formula (IV), and a compound offormula (X) under suitable conditions to provide a polymer of formula(XI).

The compounds of formula (III), (IV), and (X) can be contacted in thepresence of a solvent. Any suitable solvent can be employed. When thecompounds of formula (III), (IV), and (X) are contacted in the presenceof a solvent, the compounds of formula (III), (IV), and (X) arepreferably soluble in the solvent. One exemplary suitable solvent isN,N-dimethylacetamide.

The compounds of formula (III), (IV), and (X) can be contacted in thepresence of a base. Any suitable base can be employed. When thecompounds of formula (III), (IV), and (X) a, contacted in the presenceof a base, the base will preferably adjust the initial pH of thereaction mixture (i.e., the solution including the compounds of formula(III), (IV), and (X)) above about 7. The base is useful to yield thefree amines of the compound of formula (III) and the compound of formula(IV). One exemplary suitable base is triethylamine.

The compounds of formula (III), (IV), and (X) can be contacted for aperiod of time sufficient to provide the polymer of formula (VII). Forexample, the period of time can be from about 1 hour to about 48 hours,inclusive. Preferably, the period of time can be from about 5 hour; toabout 30 hours, inclusive. More preferably, the period of time can befrom about 10 hours to about 24 hours, inclusive.

The compounds of formula (III), (IV), and (X) can be contacted at atemperature sufficient to provide the polymer of formula (VII). Forexample, the temperature can be from about the freezing point of theliquid reaction mixture (e.g.,the solvent, base, and the compounds offormula (III), (IV), and (X)) up to about the reflux temperature of thereaction mixture. Preferably, the temperature can be from about 25° C.to about 150° C. More preferably, the temperature can be from about 50°C. to about 100° C.

The present invention will now be illustrated by the followingnon-limiting examples.

EXAMPLES

Preparation of copoly(ester amide)s (coPEAs) and copoly(ester urethane)s(coPEURs) (general procedure)

Dry triethylamine (Net₃) (30.8 mL, 0.22 mole) was added to a mixture ofpredetermined quantities of the di-p-toluenesulfonic acid salt ofbis-(L-α-amino acid)α,ω-alkylene diester (III) and thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (totalamount of (III)+(IV)=0.1 mole), and active diester (V) or activebis-carbonate (IV) (0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into cool water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure (for final purification of coPEAs andcoPEURs see below). Reduced viscosity data (η_(red)) of the polymerswere obtained in m-cresol at a concentration of 0.5 g/dL and t=25° C.

Preparation of Co-PEAs EXAMPLE 1

Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.25)} (1)(compound of formula (VII) wherein m=0.75, p=0.25, n=75, R₁=(CH₂)₄,R₂=Bz, R₃=iso-butyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (50.168 g, 0.075 mole); the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (total amount of (III)+(IV)=0.1 mole)(14.518 g, 0.025 mole); and di-p-nitrophenyl adipate (V, R¹=(CH₂)₄)(38.83 g, 0.1 mole) in dry N,N-dimethylacetamide (52.5 mL) (total volumeof DMA and NEt₃ is 83.3 ml, concentration 1.2 mol/L by (III)+(IV) or by(V)) at room temperature. Afterwards, the temperature of the reactionmixture was increased to about 80° C. and stirred for about 16 hours.The viscous reaction solution was cooled to room temperature, dilutedwith ethanol (150 mL), and poured into water. The separated polymer wasthoroughly washed with water, dried at about 30° C. under reducedpressure. After final purification up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below), yield is 90%, η_(red)=1.30 dL/g.Mw=32,100, Mn=27,000, Mw/Mn=1.19 (GPC in THF).

EXAMPLE 2

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.25)} (2)(compound of formula (VII) wherein m=0.75, p=0.25, n=65, R₁=(CH₂)₈,R₂=Bz, R₃=iso-butyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture ofdi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆)(50.168 g (0.075 mole); the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈)(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below), yield is 91%,η_(red)=1.40 dL/g. Mw=31.300, Mn=21.000, Mw/Mn=1.49 (GPC in THF).Biodegradation (weight loss in %) at 37° C. after 120 h in phosphatebuffer (pH 7.4):˜0% weight loss in pure buffer, 1-2% in the buffer withα-chymotrypsin (4 mg/10 mL of buffer), 1-2% in the buffer with lipase (4mg/10 mL of buffer).

EXAMPLE 3

Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine-1,6-hexylenediester]}_(0.50)-[N,N′-adipoyl-bis-(L-phenylalanine)-1,6-hexylenediester]_(0.25)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.25)} (3)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=(CH₂)₄, R₂=Bz,R₃=iso-butyl and Bz, and R₄=(CH₂)₆ and Bz).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonic acidsalt of bis-(L-phenylalanine)1,6-hexylene diester (III, R⁴=CH₂Ph)(18.924 g, 0.025 mole), the di-p-toluenesulfonic acid salt of L-lysinebenzyl ester (IV) (14.5180 g, 0.025 mole) (total amount of(III)+(IV)=0.1 mole), and di-p-nitrophenyl adipate (V, R¹=(CH₂)₄)(38.833, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL of)(total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification up to negative teston p-nitrophenol and p-toluenesulfonic acid (see below), yield is 94%,η_(red)=1.40 dL/g. Biodegradation (weight loss in %) at 37° C. after 120h in phosphate buffer (pH 7.4):˜0% in pure buffer, 10% in the bufferwith α-chymotrypsin (4 mg/10 mL of buffer), and 35% in the buffer withlipase (4 mg/10 mL of buffer).

EXAMPLE 4

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-[N,N′-sebacoyl-(bis-(L-phenylalanine)-1,6-hexylenediester]_(0.25)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.25)} (4)(compound of formula (VII) wherein m¹=0.50, m²=0.25, p=0.25, R¹=(CH₂)₈,R₂=Bz, R₃=iso-butyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of theof di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (34.446 g, 0.0050 mole), thedi-p-toluenesulfonic acid salt of bis-(L-phenylalanine)1,6-hexylenediester (III, R⁴=CH₂Ph) (18.924 g, 0.025 mole), the di-p-toluenesulfonicacid salt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (totalamount of (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V,R¹=(CH₂)₈) (44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification up to negative teston p-nitrophenol and p-toluenesulfonic acid (see below) yield is 95%,η_(red)=0.77 dL/g. Tg=20.6° C. (DSC).

EXAMPLE 5

Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.50)} (5)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=(CH₂)₄, R₂=Bz,R₃=iso-butyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (29.036 g, 0.050 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl adipate (V, R¹=(CH₂)₄)(38.833 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 93%,η^(red)=1.25 dL/g.

EXAMPLE 6

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.50)} (6)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=(CH₂)₈, R₂=Bz,R₃=iso-butyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (29.036 g, 0.050 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈)(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onnitrophenol and p-toluenesulfonic acid (see below) yield is 95%,η_(red)=1.31 dL/g.

EXAMPLE 7

Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)-1,8-octylenediester]}_(0.90)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.10)} (7)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₄, R₂=Bz,R₃=iso-butyl, and R₄=(CH₂)₈).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(CH₂)₈) (64.526 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl adipate (V, R¹=(CH₂)₄)(38.833, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 94%,η_(red)=1.21 dL/g.

EXAMPLE 8

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,4-butylenediester]}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (8)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-butyl, and R₄=(CH₂)₄).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylene diester(III, R⁴=(CH₂)₄) (59.477 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole (total amount of(III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈)(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL of)(total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into water. Theseparated polymer was thoroughly washed with water, dried at 30° C.under reduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 95%,η_(red)=1.28 dL/g.

EXAMPLE 9

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (9)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-butyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (62.002 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈)(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 96%,η_(red)=1.41 dL/g. Biodegradation (weight loss in %) at 37° C. after 120h in phosphate buffer (pH 7.4):˜0% in pure buffer, 12% in the bufferwith α-chymotrypsin (4 mg/10 mL of buffer), and 38% in the buffer withlipase (4 mg/10 mL of buffer).

EXAMPLE 10

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,8-octylenediester]}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (10)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-butyl, and R₄=(CH₂)₈).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(CH₂)₈) (64.526 g, 0.0090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈)(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 97%,η_(red)=1.50 dL/g. Tg 27.5° C. (DSC).

EXAMPLE 11

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,12-dodecylenediester]}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (11)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-butyl, and R₄=(CH₂)₁₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,12-dodecylenediester (III, R⁴=(CH₂)₁₂) (69.576 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.010 mole) (total amount of (III)+(IV)=0.1 mole), and di-p-nitrophenylsebacinate (V, R¹=(CH₂)₈) (44.444 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (V)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification, yield is 96% up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below), η_(red)=0.68 dL/g.

EXAMPLE 12

Preparation ofco-poly-{[N,N′-dodecyldicarboxyloyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.90)-{[N,N′-dodecyldicarboxyloyl-L-lysine benzylester]_(0.10)} (12) (compound of formula (VII) wherein m=0.90, p=0.10,R₁=(CH₂)₁₂, R₂=Bz, R₃=iso-butyl, and R₄=(CH₂)₆.

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (62.002 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole (total amount of(III)+(IV)=0.1 mole), and di-p-nitrophenyl dodecyldicarboxylate (V,R¹=(CH₂)₁₂) (50.055 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA)(52.5 mL) (total volume of DMA and NEt₃ in 83.3 mL, concentration 1.2mol/L by (III)+(IV) or by (V)) at room temperature. Afterwards thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, diluted with ethanol (150 mL), and poured into water.The separated polymer was thoroughly washed with water, dried at 30° C.under reduced pressure. After final purification yield is 96% up tonegative test on p-nitrophenol and p-toluenesulfonic acid (see below),η_(red)=1.18 dL/g.

Preparation of Co-PEURs:

EXAMPLE 13

Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)-1,4-butylenediester]}_(0.75)-{[N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25) } (13) (compound of formula (XI) wherein m=0.75, p=0.25,R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₄), and R₆=(CH₂)₃.

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylene diester(III, R⁴=(CH₂)₄) (49.565 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X) (R⁶=(CH₂)₃)(40.624 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ in 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (X)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature, andpoured into water. The separated polymer was thoroughly washed withwater, dried at 30° C. under reduced pressure. After final purificationup to negative test on p-nitrophenol and p-toluenesulfonic acid (seebelow) yield is 63%, η_(red)=0.32 dL/g.

EXAMPLE 14

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,4-butylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.25)} (14) (compound of formula (XI) wherein m=0.75,p=0.25, R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₄), and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylene diester(III, R⁴=(CH₂)₄) (49.565 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, and poured into water. The separated polymer wasthoroughly washed with water, dried at about 30° C. under reducedpressure After final purification up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below) yield is 78%, η_(red)=0.58 dL/g.Biodegradation (weight loss in %) at 37° C. after 240 h in phosphatebuffer (pH 7.4): 4.7% in pure buffer, 2.2% in the buffer withα-chymotrypsin (4 mg/10 mL, of buffer), 4.4% in the buffer with lipase(4 mg/10 mL of buffer). Films with d=4 cm and m=500±50 mg on Teflonbacking.

EXAMPLE 15

Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25)} (15) (compound of formula (XI) wherein m=0.75, p=0.25,n=112, R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₆), and R₆=(CH₂)₃.

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (51.668 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X) (R⁶=(CH₂)₃)(40.624 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (X)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature, andpoured into water. The separated polymer was thoroughly washed withwater, dried at about 30° C. under reduced pressure, After finalpurification up to negative test on p-nitrophenol and p-toluenesulfonicacid (see below) yield is 60%, η_(red)=0.53 dL/g. Mw=50,000, Mn=29,900,M_(w)/M_(n)=1.68 (GPC). Biodegradation (weight loss in %) at 37° C.after 180 h in phosphate buffer (pH 7.4): 5.0% in pure buffer, 7.3% inthe buffer with α-chymotrypsin (4 mg/10 mL of buffer), and 8.2% in thebuffer with lipase (4 mg/10 mL of buffer). Films with d=4 cm andm=500±50 mg on Teflon backing.

EXAMPLE 16

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.25)} (16) (compound of formula (XI) wherein m=0.75,p=0.25, n=130, R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₆), and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (51.668 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature.

Afterwards, the temperature of the reaction mixture was increased toabout 80° C. and stirred for about 16 hours. The viscous reactionsolution was cooled to room temperature, and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification up to negative teston p-nitrophenol and p-toluenesulfonic acid (see below) yield is 68%,η_(red)=0.72 dL/g. Mw=61,900, Mn=38,500, Mw/Mn=1.61 (GPC).Biodegradation (weight loss in %) at 37° C. after 180 h in phosphatebuffer (pH 7.4): 4.0% in pure buffer, 5.6% in the buffer withα-chymotrypsin (4 mg/10 mL of buffer), and 8.9% in the buffer withlipase (4 mg/10 mL of buffer). Films with d=4 cm and m=500±50 mg onTeflon backing.

EXAMPLE 17

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.50)} (17) (compound of formula (XI) wherein m=0.50,p=0.50, n=85, R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₆), and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture ofdi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (29.036 g, 0.050 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, and poured into water. The separated polymer wasthoroughly washed with water, dried at about 30° C. under reducedpressure. After final purification up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below) yield is 80%, η_(red)=0.45 dL/g.M_(w)=37,900, M_(n)=22,300, Mw/Mn=1.70 (GPC).

EXAMPLE 18

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.90)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.10)} (18) (compound of formula (XI) wherein m=0.90,p=0.10, n=115, R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₆), and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (62.002 g, 0.90 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature.

Afterwards, the temperature of the reaction mixture was increased toabout 80° C. and stirred for about 16 hours. The viscous reactionsolution was cooled to room temperature, and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification up to negative teston p-nitrophenol and p-toluenesulfonic acid (see below) yield is 70%,η_(red)=0.74 dL/g. M_(w)=56,500, M_(n)=33,700, M_(w)/M_(n)=1.68 (GPC).

EXAMPLE 19

Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)-1,8-octylenediester]}_(0.75)-{[N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25) } (19) (compound of formula (XI) wherein m=0.75, p=0.25,R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₈), and R₆=(CH₂)₃.

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(CH₂)₈) (53.772 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X) (R⁶=(CH₂)₃)(40.624 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (X)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature, andpoured into water. The separated polymer was thoroughly washed withwater, dried at about 30° C. under reduced pressure. After finalpurification up to negative test on p-nitrophenol and p-toluenesulfonicacid (see below) yield is 84%, η_(red)=0.46 dL/g. Biodegradation (weightloss in %) at 37° C. after 240 h in phosphate buffer (pH 7.4): 0.9% inpure buffer, 2.0% in the buffer with α-chymotrypsin (4 mg/10 mL ofbuffer), and 3.7% in the buffer with lipase (4 mg/10 mL of buffer).Films with d=4 cm and m=500±50 mg on Teflon backing.

EXAMPLE 20

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,8-octylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.25)} (20) (compound of formula (XI) wherein m=0.75,p=0.25, R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₈), and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(CH₂)₈) (53.772 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂)(43.63 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards thetemperature of the reaction mixture was increased to about 80° C. andstirred for 16 hours. The viscous reaction solution was cooled to roomtemperature, and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification, yield is 76% up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below), η_(red)=0.42 dL/g.

EXAMPLE 21

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,8-octylenediester]}_(0.90)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.10)} (21) (compound of formula (XI) wherein m=0.90,p=0.10, R₂=Bz, R₃=iso-butyl, R₄=(CH₂)₈) and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(CH₂)₈) (64.5264 g, 0.09 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.8072 g, 0.01 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂)(43.63 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards thetemperature of the reaction mixture was increased to about 80° C. andstirred for 16 hours. The viscous reaction solution was cooled to roomtemperature, and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification up to negative test on p-nitrophenol andp-toluenesulfonic acid (see below) yield is 63%, η_(red)=0.51 dL/g.

EXAMPLE 22 Deprotection of Polymeric Benzyl Esters (general procedure)

According to the general procedure described herein for the preparationof coPEAs and coPEURs, the polymers were obtained as the benzyl esterforms. For the preparation of the corresponding polymers having freeCOOH groups, these polymers having the benzyl esters were subjected tocatalytic debenzylation using hydrogen (H₂) gas and palladium (Pd) blackas a catalyst. Suitable reaction conditions are available, e.g., in T.W. Greene, Protecting Groups In Organic Synthesis; Wiley: New York,1981; J. March, Advanced Organic Chemistry, Reactions, Mechanisms andStructure, (2nd Ed.), McGraw Hill: New York, 1977; F. Carey and R.Sundberg, Advanced Organic Chemistry, Part B: Reactions and Synthesis,(2nd Ed.), Plenum: New York, 1977; and references cited therein.

(A.) Deprotection of Polymeric Benzyl Esters (coPEAs)

Palladium black catalyst (3.0 g) was added to a solution of the polymer(benzyl ester form) (10 g) in ethanol (100 mL), and dry gaseous hydrogenwas bubbled through the solution for about 10 hours to about 20 hours. Amagnetic stirrer was used to agitate the solution. After catalytichydrogenolysis was complete, the reaction mixture was filtered, andclear and colorless solutions were obtained.

(B.) Deprotection of Polymeric Benzyl Esters (coPEURs)

Palladium black catalyst (3.0 g) was added to a solution of the polymer(benzyl ester form) (10 g) in ethyl acetate (100 mL), and dry gaseoushydrogen was bubbled through the solution for about 10 hours to about 30hours. A magnetic stirrer was used to agitate the solution. Aftercatalytic hydrogenolysis was complete, the reaction mixture wasfiltered, and clear and colorless solutions were obtained.

After deprotection of the polymers, no substantial change of molecularweight or polydispersity was observed. For example, for the compound (2)from Table 3 (i.e., benzyl ester form) the molecular weightcharacteristics were as follows: Mw=31.300, Mn=21.000, Mw/Mn=1.49. Afterhydrogenolysis, molecular weight characteristics are: Mw=40.900,Mn=28.000, and Mw/Mn=1.46.

EXAMPLE 23 Purification of the Benzyl Ester Polymers (Generalprocedures)

After the polymers were precipitated in water and thoroughly washed withwater, the solvent (DMA) and p-toluenesulfonic acid salt oftriethylamine were removed (nearly to completion). However, the polymersstill contain a significant amount of by-product of the polycondensation(e.g., p-nitrophenol) which was removed as described below.

(A.) Purification of coPEAs

The polymer obtained above (10 g) was dissolved in ethanol (50 mL, 95%).The solution was filtered and the polymer was precipitated in ethylacetate (1.0 L), where it separates as tar like mass, and was keptovernight in refrigerator. The ethyl acetate was removed and a freshportion of ethyl acetate (1.0 L) was added to the tar like mass and keptovernight in refrigerator again. This procedure was repeated until anegative test on p-nitrophenol (see below) was obtained. Normally it wasrepeated for 1-2 times. After such a treatment, p-nitrophenol (which ismore soluble in ethylacetate than in water), was nearly completelyremoved from the polymers. The obtained tar like mass was dried,dissolved in 95% ethanol, precipitated in distilled water as arubber-like mass, and dried at about 60° C. under reduced pressure.Yields of purified coPEAs were up to about 97%.

(B.) Purification of coPEURs

The polymer obtained above (10 g) was dissolved in chloroform (100 mL),cast as a thin film onto a cylindrical glass vessel's (d=400-500 mm)inner surface, dried at room temperature, thoroughly washed with water,and dried again. The film obtained was dissolves in dimethylformamide(DMF), and the polymer was precipitated in water. A rubber-like polymerwas collected and dried at about 35° C. to about 40° C. under reducedpressure. This procedure was repeated for several times, until anegative test on p-nitrophenol was obtained (see below). Normally it wasrepeated about 3-4 times. After such a treatment, the yields of coPEURsdecreased to ≦80%, however the viscosities increased, which is believedto be the result of the loss of low-molecular-weight fractions.

(C.) Purification of Deprotected Polymers (polyacids)

After deprotection, polymers were purified by precipitation from anethanol solution in water. A rubber-like mass was collected and dried atroom temperature under reduced pressure.

EXAMPLE 25 4-AminoTEMPO Attachment and its Biodegradation and FreeRadicals Release Study

For this study the co-PEA of the following structure was chosen:

(The hydrogenolysis product of the Example 2) which revealed excellentelasticity (elongation at break ca. 1000%) and was used in in vivo“stent experiments”.

4-AminoTEMPO (TAM) was attached to this polyacid usingcarbonyldiimidazol (Im₂CO) as a condensing agent. In typical procedure 1g of polyacid was dissolved in 10 mL of purified, freshly distilledchloroform. A molar equivalent of carbonyldiimidazole was added at roomtemperature and stirred. A molar equivalent of TAM was added, stirredfor 4 h, and kept at r. t. overnight. The solution was filtered and castonto a hydrophobic surface. Chloroform was evaporated to dryness. Theobtained film was thoroughly washed with distilled water and dried underreduced pressure at r. t. An elastic, light red-brown film was obtained.The degree of TAM attachment was 90-95%, determined by UVspectrophotometry in ethanol solution at 250 nm (Polymer does not absorbat this wavelength).

After TAM attachment, the polymer retained elastic properties. Itdegraded by lipase according to nearly zero order biodegradationkinetics (that is ideal for drug controlled release devices) whileretaining the film's integrity whereas the starting polyacid completelydegraded and/or disintegrated within 48 h in slightly alkaline buffersolution in the presence of lipase). TAM attached polymer is designatedas GJ-2(TAM).

For the biodegradation study, the film of GJ-2(TAM) was obtained, it wasdissolved in 10 mL of chloroform, and a Teflon disk of d=4 cm wascovered by this solution for several times and evaporated so that theweight of dried polymeric coating was ca. 500 mg. The disc was placed ina lipase solution (4 mg of the enzyme in 10 mL of phosphate buffer withpH 7.4. 6 mL of the enzyme was dissolved in 15 mL of the buffer—10 mLwas used for biodegradation experiment, 5 mL—for the compensation in UVmeasurements) and placed in thermostat at 37° C. The enzyme solution waschanged every 24 h. Every 24 h the film was removed, dried with filerpaper and weighed. The buffer solution was analyzed by UV-spectroscopyat 250 nm since the polymeric degradation products don't absorb at thiswavelength. The same solution of the enzyme was used for thecompensation.

The obtained results indicate that both biodegradation (weight loss) ofthe polymer and TAM releasing are very close to zero order kinetics.

Since the amide bond through which the TAM is attached to the polymer israther stable under the biodegradation conditions, it is expected thatTAM is released to the polymeric debris. At the same time thecalibration curve of TAM in buffer was used for quantitativemeasurements. Therefore, the amount of TAM (in mg), determined byUV-spectroscopy, corresponds to the free TAM in mg (in mg/equivalent).

After 216 h (9 days) biodegradation polymer lost ca. 11% of the weight,and ca. 8% of the attached TAM was released. This, along withbiodegradation and TAM releasing profiles, indicates that the TAMreleasing is determined by the erosion of the polymeric film.

The results of the biodegradation (weight loss in mg/cm²) of4-AmimoTEMPO (TAM), attached to a co-PEA of the present invention, andthe kinetics of nitroxyl radical release from 4-AminoTEMPO (TAM),attached to a co-PEA of the present invention, are shown in the chartsbelow. Chart 1 illustrates the biodegradation (weight loss in mg/cm²) of4-Amino TEMPO (TAM) attached to a representative compound of the presentinvention. Chart 2 illustrates the kinetics of nitroxyl radical releasefrom 4-Amino TEMPO (TAM) attached to a representative compound of thepresent invention.

Time weight loss hours mg/cm² 0 0 24 0.22 48 0.47 72 0.85 120 1.5 1441.71 168 1.85 192 2.23 216 2.42 CHART 1 Lipase catalyzed biodegradation(weight loss in mg/cm₂) of TAM-attached co-PEA [GJ- 2(TAM)]

Time Nitroxy radical released hours mg equivalents of TAM 0 0 24 0.95 481.4 96 1.93 120 2.2 144 2.5 168 2.97 192 3.2 216 3.7 CHART 2 Kinetics ofnitroxyl radical releasing from TAM attached co-PEA

EXAMPLE 24 Test on Purity (general procedure)

The coPEA or coPEUR (200-250 mg) was dissolved in a boiling 10% watersolution of NaOH (5.0 mL), and the resulting solution was analyzed usingUV-VIS spectrophotometer (Specord UV-VIS, Carl Zeiss, Jena, cell of 4mL, 1=1,0 cm). The absence of the absorption in the region of 250-280 nm(TosO⁻) and at 430 nm (O₂NC₆H₄O⁻) indicates that neitherp-toluenesulfonic acid nor p-nitrophenol exists in the polymeric sampleto any appreciable degree. It is noted that in alkaline media,p-nitrophenol does not absorb in UV region. As such, its absorption doesnot overlap the absorption of p-toluenesulfonic acid.

The structure of the benzylated polymers prepared in Examples 1-21 isgiven in the Tables below.

TABLE I Example 25

(VII) Compound R₁ R₂ R₃ R₄ m p n (1) (CH₂)₄ Bz iso-butyl (CH₂)₆ 0.750.25 75 (2) (CH₂)₈ Bz iso-butyl (CH₂)₆ 0.75 0.25 65 (3) (CH₂)₄ Bziso-butyl and Bz (CH₂)₆ 0.75 (0.50 + 0.25) 0.25 — (4) (CH₂)₈ Bziso-butyl (CH₂)₆ 0.75 (0.50 + 0.25) 0.25 — (5) (CH₂)₄ Bz iso-butyl(CH₂)₆ 0.50 0.50 — (6) (CH₂)₈ Bz iso-butyl (CH₂)₆ 0.50 0.50 — (7) (CH₂)₄Bz iso-butyl (CH₂)₈ 0.90 0.10 — (8) (CH₂)₈ Bz iso-butyl (CH₂)₄ 0.90 0.10— (9) (CH₂)₈ Bz iso-butyl (CH₂)₆ 0.90 0.10 — (10)  (CH₂)₈ Bz iso-butyl(CH₂)₈ 0.90 0.10 — (11)  (CH₂)₈ Bz iso-butyl  (CH₂)₁₂ 0.90 0.10 — (12)  (CH₂)₁₂ Bz iso-butyl (CH₂)₆ 0.90 0.10 —

TABLE II Example 26

(XI) Compound R₂ R₃ R₄ R₆ m p n (13) Bz iso-butyl (CH₂)₄ (CH₂)₃ 0.750.25 — (14) Bz iso-butyl (CH₂)₄ (CH₂)₂—O—(CH₂)₂ 0.75 0.25 — (15) Bziso-butyl (CH₂)₆ (CH₂)₃ 0.75 0.25 112 (16) Bz iso-butyl (CH₂)₆(CH₂)₂—O—(CH₂)₂ 0.75 0.25 130 (17) Bz iso-butyl (CH₂)₆ (CH₂)₂—O—(CH₂)₂0.50 0.50  85 (18) Bz iso-butyl (CH₂)₆ (CH₂)₂—O—(CH₂)₂ 0.90 0.10 115(19) Bz iso-butyl (CH₂)₈ (CH₂)₃ 0.75 0.25 — (20) Bz iso-butyl (CH₂)₈(CH₂)₂—O—(CH₂)₂ 0.75 0.25 — (21) Bz iso-butyl (CH₂)₈ (CH₂)₂—O—(CH₂)₂0.90 0.10 —

TABLE III The physical properties of the polymers prepared in Examples1-12 are given in Table III. Example 27 Mw/Mn (GPC Tg Compound Yield (%)η _(red)(dL/g) Mw Mn in THF) B.W.L. (%)¹ B.W.L. (%)² B.W.L. (%)³ (DSC) (1) 90 1.30 32,100 27,000 1.19  (2) 91 1.40 31,300 21,000 1.49 ˜0 1-21-2  (3) 94 1.40 ˜0 10 35  (4) 95 0.77 20.6° C.  (5) 93 1.25  (6) 951.31  (7) 94 1.21  (8) 95 1.28  (9) 96 1.41 ˜0 12 38 (10) 97 1.50 27.5°C. (11) 96 0.68 (12) 96 1.18 (13) 63 0.32 (14) 78 0.58 4.7⁴ 2.2⁵ 4.4⁶(15) 60 0.53 50,000 29,900 1.68 5.0⁷ 7.3⁸ 8.2⁹ (16) 68 0.72 61,90038,500 1.61 0.4⁷ 5.6⁸ 8.9⁹ (17) 80 0.45 37,900 22,300 1.70 (18) 70 0.7456,500 33,700 1.68 (19) 84 0.46 0.9⁴ 2.0⁵ 3.7⁶ (20) 76 0.42 (21) 63 0.51¹B.W.L. (%) is biodegradation (weight loss %) at 37° C. after 120 h inphosphate buffer (pH 7.4). ²B.W.L. (%) is biodegradation (weight loss %)at 37° C. after 120 h in phosphate buffer (pH 7.4) with α-chymotrypsin(4 mg/10 mL of buffer. ³B.W.L. (%) is biodegradation (weight loss %) at37° C. after 120 h in phosphate buffer (pH 7.4) with lipase (4 mg/10 mLof buffer). ⁴B.W.L. (%) is biodegradation (weight loss %) at 37° C.after 240 h in phosphate buffer (pH 7.4). ⁵B.W.L. (%) is biodegradation(weight loss %) at 37° C. after 240 h in phosphate buffer (pH 7.4) withα-chymotrypsin (4 mg/10 mL of buffer. ⁶B.W.L. (%) is biodegradation(weight loss %) at 37° C. after 240 h in phosphate buffer (pH 7.4) withlipase (4 mg/10 mL of buffer). ⁷B.W.L. (%) is biodegradation (weightloss %) at 37° C. after 180 h in phosphate buffer (pH 7.4). ⁸B.W.L. (%)is biodegradation (weight loss %) at 37° C. after 180 h in phosphatebuffer (pH 7.4) with α-chymotrypsin (4 mg/10 mL of buffer. ⁹B.W.L. (%)is biodegradation (weight loss %) at 37° C. after 180 h in phosphatebuffer #H 7.4) with lipase (4 mg/10 mL of buffer).

The benzylated polymers obtained had high Mw in the range 30,000-60,000and narrow polydispersity—Mw/Mn=1.2-1.7 (Determined by GPC for thepolymers, soluble in THF), and possess excellent film-formingproperties. They revealed rather low glass transition temperature(Tg=9-20° C.). The polymers are soluble in common organic solvents likechloroform (all of them), ethanol, (copoly(ester amide)s), ethylacetate(copoly(ester urethane)s), some of them in THF. Both co-PEAs andco-PEURs reveal rather high tendency to in vitro biodegradation. Co-PEAsare more inclined to specific (enzyme catalyzed) hydrolysis, whereasco-PEURs showed the tendency to both specific and non-specific(chemical) hydrolysis.

EXAMPLE 28 In Vitro Biodegradation Study

In vitro biodegradation studies were performed by weight loss. Standardfilms with d=4 cm and m=450-550 mg (pure films in case ofnon-contractive poly(ester amide)s and films on Teflon backing in caseof contractive poly(ester urethane)s), were placed into the glassvessels containing 10 mL of 0.2 M phosphate buffer solution with pH=7.4(either pure buffer or buffer containing 4 mg of anenzyme—α-chymotrypsin or lipase) and placed at 37° C. The films wereremoved from the solutions after a predetermined time, dried with filterpaper and weighted. Buffer or enzyme solution was changed every 24 h.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A polymer of formula (VII):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R¹ is independently (C₂-C₂₀)alkyl; each R²is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ isindependently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; and each R⁴ is independently (C₂-C₂₀)alkyl. 2.The polymer of claim 1 wherein each R¹ is independently (CH₂)₄, (CH₂)₈,or (CH₂)₁₂.
 3. The polymer of claim 1 wherein each R² is independentlyhydrogen or benzyl.
 4. The polymer of claim 1 wherein each R³ isindependently iso-butyl or benzyl.
 5. The polymer of claim 1 whereineach R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 6. Thepolymer of claim 1 wherein p/(p+m) is about 0.9 to about 0.1.
 7. Thepolymer of claim 1 wherein m/(p+m) Is about 0.1 to about 0.9.
 8. Apolymer of formula (VII) comprising one or more subunits of the formula(I):

wherein R¹ is independently (C₂-C₂₀)alkyl; and R² is independentlyhydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and one or more subunits of theformula (II):

wherein each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and R⁴ is independently(C₂-C₂₀)alkyl.
 9. The polymer of claim 8 wherein R¹ is independently(CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 10. The polymer of claim 8 wherein R² isindependently hydrogen or benzyl.
 11. The polymer of claim 8 whereineach R³ is independently iso-butyl or benzyl.
 12. The polymer of claim 8wherein R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 13. Thepolymer of claim 8 that is a polymer of formula (VII):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; and nis about 50 to about
 150. 14. The polymer of claim 13 wherein p/(p+m) isabout 0.9 to about 0.1.
 15. The polymer of claim 13 wherein m/(p+m) isabout 0.1 to about 0.9.
 16. A polymer of formula (VII) formed from anamount of one or more compounds of formula (III):

wherein each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and R⁴ is independently(C₂-C₂₀)alkyl; or a suitable salt thereof; an amount of one or morecompounds of formula (IV):

wherein R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or asuitable salt thereof; and an amount of one or more compounds of formula(V):

wherein R¹ is independently (C₂-C₂₀)alkyl; and each R⁵ is independently(C₆-C₁₀)aryl optionally substituted with one or more nitro, cyano, halo,trifluoromethyl, or trifluoromethoxy.
 17. The polymer of claim 16wherein R¹ is independently (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 18. The polymerof claim 16 wherein R² is independently hydrogen or benzyl.
 19. Thepolymer of claim 16 wherein each R³ is independently iso-butyl orbenzyl.
 20. The polymer of claim 16 wherein R⁴ is independently (CH₂)₄,(CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 21. The polymer of claim 16 wherein each R⁵is p-nitrophenyl.
 22. The polymer of claim 16 wherein the compound offormula (III) is the di-p-tolunesulfonic acid salt of a bis-(L-α-aminoacid)-α,ω-alkylene diester.
 23. The polymer of claim 16 wherein thecompound of formula (IV) is the di-p-tolunesulfonic acid salt ofL-lysine benzyl ester.
 24. The polymer of claim 16 wherein the compoundof formula (V) is di-p-nitrophenyl adipate, di-p-nitrophenyl sebacinate,or di-p-nitrophenyl dodecyldicarboxylate.
 25. The polymer of claim 16that is a polymer of formula (VII):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; and nis about 50 to about
 150. 26. The polymer of claim 25 wherein p/(p+m) isabout 0.9 to about 0.1.
 27. The polymer of claim 25 wherein m/(p+m) isabout 0.1 to about 0.9.
 28. A method for preparing a polymer of formula(VII):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R¹ is independently (C₂-C₂₀)alkyl; each R²is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ isindependently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; and each R⁴ is independently (C₂-C₂₀)alkyl;comprising contacting an amount of one or more compounds of formula(III):

or a suitable salt thereof; an amount of one or more compounds offormula (IV):

or a suitable salt thereof; and an amount of one or more compounds offormula (V):

wherein each R⁵ is independently (C₆-C₁₀)aryl optionally substitutedwith one or more nitro, cyano, halo, trifluoromethyl, ortrifluoromethoxy; under suitable conditions to provide the polymer offormula (VII).
 29. The method of claim 28 wherein each R¹ isindependently (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 30. The method of claim 28wherein each R² is independently hydrogen or benzyl.
 31. The method ofclaim 28 wherein each R³ is independently iso-butyl or benzyl.
 32. Themethod of claim 28 wherein each R⁴ is independently (CH₂)₄, (CH₂)₆,(CH₂)₈, or (CH₂)₁₂.
 33. The method of claim 28 wherein each R⁵ isp-nitrophenyl.
 34. The method of claim 28 wherein the compound offormula (III) is the di-p-tolunesulfonic acid salt of a bis-(L-α-aminoacid)-α,ω-alkylene diester.
 35. The method of claim 28 wherein thecompound of formula (IV) is the di-p-tolunesulfonic acid salt ofL-lysine benzyl ester.
 36. The method of claim 28 wherein the compoundof formula (V) is di-p-nitrophenyl adipate, di-p-nitrophenyl sebacinate,or di-p-nitrophenyl dodecyldicarboxylate.
 37. The method of claim 28wherein the contacting is carried out in the presence of a base.
 38. Themethod of claim 37 wherein the base is triethylamine.
 39. The method ofclaim 28 wherein the contacting is carried out in the presence of asolvent.
 40. The method of claim 39 wherein the solvent isN,N-dimethylacetamide.
 41. The method of claim 28 wherein the contactingis carried out at about 50° C. to about 100° C.
 42. The method of claim28 wherein the contacting occurs for about 10 hours to about 24 hours.43. The method of claim 28 further comprising purifying the polymer offormula (VII).
 44. The method of claim 28 wherein p/(p+m) is about 0.9to about 0.1.
 45. The method of claim 28 wherein m/(p+m) is about 0.1 toabout 0.9.
 46. A polymer of formula (XI):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R² is independently hydrogen, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R⁴ is independently (C₂-C₂₀)alkyl; andeach R⁶ is independently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl.47. The polymer of claim 46 wherein each R² is independently hydrogen orbenzyl.
 48. The polymer of claim 46 wherein each R³ is independentlyiso-butyl or benzyl.
 49. The polymer of claim 46 wherein each R⁴ isindependently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 50. The polymer ofclaim 46 wherein each R⁶ is independently (CH₂)₃ or (CH₂)₂—O—(CH₂)₂. 51.The polymer of claim 46 wherein p/(p+m) is about 0.9 to about 0.1. 52.The polymer of claim 46 wherein m/(p+m) is about 0.1 to about 0.9.
 53. Apolymer of formula (XI) comprising one or more subunits of the formula(VIII):

wherein each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and R⁴ is independently(C₂-C₂₀)alkyl; R⁶ is independently (C₂-C₂₀)alkyl or(C₂-C₈)alkyloxy(C₂-C₂₀)alkyl; and one or more subunits of the formula(IX):

 wherein R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl. 54.The polymer of claim 53 wherein R² is independently hydrogen or benzyl.55. The polymer of claim 53 wherein each R³ is independently iso-butylor benzyl.
 56. The polymer of claim 53 wherein R⁴ is independently(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 57. The polymer of claim 53 whereinR⁶ is independently (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.
 58. The polymer of claim53 that is a polymer of formula (XI):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R² is independently hydrogen, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R⁴ is independently (C₂-C₂₀)alkyl; eachR⁵ is independently (C₆-C₁₀)aryl optionally substituted with one or morenitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and each R⁶ isindependently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl.
 59. Apolymer of formula (XI) formed from an amount of one or more compoundsof formula (III):

wherein each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and R⁴ is independently(C₂-C₂₀)alkyl; or a suitable salt thereof; an amount of one or morecompounds of formula (IV):

wherein R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or asuitable salt thereof; and an amount of one or more compounds of formula(X):

wherein each R⁵ is independently (C₆-C₁₀)aryl optionally substitutedwith one or more nitro, cyano, halo, trifluoromethyl, ortrifluoromethoxy; and R⁶ is independently (C₂-C₂₀)alkyl or(C₂-C₈)alkyloxy(C₂-C₂₀)alkyl.
 60. The polymer of claim 59 wherein R² isindependently hydrogen or benzyl.
 61. The polymer of claim 59 whereineach R³ is independently iso-butyl or benzyl.
 62. The polymer of claim59 wherein R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂. 63.The polymer of claim 59 wherein each R⁵ is p-nitrophenyl.
 64. Thepolymer of claim 59 wherein R⁶ is independently (CH₂)₃ or(CH₂)₂—O—(CH₂)₂.
 65. The polymer of claim 59 wherein the compound offormula (III) is the di-p-tolunesulfonic acid salt of a bis-(L-α-aminoacid)-α,ω-alkylene diester.
 66. The polymer of claim 59 wherein thecompound of formula (IV) is the di-p-tolunesulfonic acid salt ofL-lysine benzyl ester.
 67. The polymer of claim 59 wherein the compoundof formula (X) is 1,3-bis(4-nitro-phenoxycarbonyloxy)propane; or2,2′-bis-4-nitrophenoxycarbonyloxy ethylether.
 68. The polymer of claim59 that is a polymer of formula (XI):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; and nis about 50 to about
 150. 69. The polymer of claim 68 wherein p/(p+m) isabout 0.9 to about 0.1.
 70. The polymer of claim 68 wherein m/(p+m) isabout 0.1 to about 0.9.
 71. A method for preparing a polymer of formula(XI):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R² is independently hydrogen, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R⁴ is independently (C₂-C₂₀)alkyl; eachR⁵ is independently (C₆-C₁₀)aryl optionally substituted with one or morenitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and each R⁶ isindependently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl; comprisingcontacting an amount of one or more compounds of formula (III):

or a suitable salt thereof; an amount of one or more compounds offormula (IV):

or a suitable salt thereof; and an amount of one or more compounds offormula (X):

under suitable conditions to provide the polymer of formula (XI). 72.The method of claim 71 wherein each R² is independently hydrogen orbenzyl.
 73. The method of claim 71 wherein each R³ is independentlyiso-butyl or benzyl.
 74. The method of claim 71 wherein each R⁴ isindependently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 75. The method ofclaim 71 wherein each R⁵ is p-nitrophenyl.
 76. The method of claim 71wherein each R⁶ is independently (CH₂)₃ or (CH₂)₂—O—(CH₂)₁₂.
 77. Themethod of claim 71 wherein the compound of formula (III) is thedi-p-tolunesulfonic acid salt of a bis-(L-α-amino acid)-α,ω-alkylenediester.
 78. The method of claim 71 wherein the compound of formula (IV)is the di-p-tolunesulfonic acid salt of L-lysine benzyl ester.
 79. Themethod of claim 71 wherein the compound of formula (X) is1,3-bis(4-nitro-phenoxycarbonyloxy)propane; or2,2′-bis-4-nitrophenoxycarbonyloxy ethylether.
 80. The method of claim71 wherein the contacting is carried out in the presence of a base. 81.The method of claim 80 wherein the base is triethylamine.
 82. The methodof claim 71 wherein the contacting is carried out in the presence of asolvent.
 83. The method of claim 82 wherein the solvent isN,N-dimethylacetamide.
 84. The method of claim 71 wherein the contactingis carried out at about 50° C. to about 100° C.
 85. The method of claim71 wherein the contacting occurs for about 10 hours to about 24 hours.86. The method of claim 71 further comprising purifying the polymer offormula (XI).
 87. The method of claim 71 wherein p/(p+m) is about 0.9 toabout 0.1.
 88. The method of claim 71 wherein m/(p+m) is about 0.1 toabout 0.9.
 89. A method of using a polymer of any one of claims 1-70 foruse as a medical device, a pharmaceutical, a carrier for covalentimmobilization of a drug, or a bioactive substance.
 90. A method ofusing a polymer of any one of claims 1-70 for the manufacture of amedical device, a pharmaceutical, a carrier for covalent immobilizationof a drug, or a bioactive substance.